Peptides are ubiquitous biological molecules and have, in recent years, become the subject of extensive research and investigation. For example, the possibilities for utilizing natural biological substances, such as peptides, as therapeutics for various disease states is being aggressively explored.
Elucidation of the amino acid sequences of such peptides such as Growth Hormone, Growth Hormone Releasing Factor, or Cholecystokinin (CCK) has lead to advancements in the understanding of how these molecules work in treating various disorders. However, peptides are generally poorly adsorbed and suffer from rapid degradation upon exposure to peptidases often resulting in low bioavailability. It has been recently discovered that in many instances if the amino acid constituency of many naturally occurring peptides is altered by single or multiple amino acid substitutions at different sites, the analogs of the natural peptide may have better bioavailability or degrade less rapidly and hence exhibit greater efficacy.
For example, CCK is a family of peptide hormones which vary in length up to 58 amino acids. The sequence of CCK first isolated contained 33 amino acids (CCK-33). CCK-33 as well as fragments thereof, such as CCK-8 and Acetyl-CCK-7, have been shown to have satietyinducing effects when administered peripherally to animals. CCK-8 has the amino acid sequence: EQU Asp.sup.26 -Tyr-(SO.sub.3 H).sup.27 -Met.sup.28 -Gly.sup.29 -Trp.sup.30 -Met.sup.31 -Asp.sup.32 -Phe.sup.33 -NH.sub.2.
CCK-7 lacks the amino acid Asp in position 26.
While CCK analogs are known to have satiety inducing effects, they are not selective and also exhibit low bioavailability. This has led to the synthesis of various CCK analogs wherein the attempt to improve properties such as stability and bioavailability has been made. A multitude of CCK analogs with various amino acid substitutions have yielded compounds with altered properties which enhance their potential usefulness in human therapeutics.